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In my last post, I introduced the problem of antibiotic resistance. It’s important to note that resistance is something developed over time – some bacteria were never susceptible to certain antibiotics in the first place. For instance, if I’m one of the three little pigs, and I build my house out of bricks, all the huffing and puffing of one wolf isn’t really going to make much difference. Neither will fire. But if I’d built it out of logs, I might be safe from the wolf’s breath, but not from flames. Susceptibility is about what drugs can be effectively used against a pathogen, or cause of disease. Resistance is about the ability of a pathogen to lose susceptibility to a drug that was previously effective. If it never worked, the pathogen isn’t resistant.

That’s an important distinction because bacteria, when they share, can share resistance factors (plasmids) for antibiotics without any consideration for their own susceptibility. Jim, the reeking Escherichia, can pick up a plasmid for resistance to penicillin. It does Jim no good – Jim was never susceptible in the first place. The mechanisms that penicillin uses to attack bacteria, the specific protein structures that penicillin targets, aren’t present on Jim. Penicillin can’t target what isn’t present. But Jim can still take the plasmid, tuck it away, and share freely. Jim shares resistance that he doesn’t need – which, as I said before, is an enormous problem. I also said there was a bigger problem – you and I helping the bacteria.

Your doctor prescribes antibiotics. Now, there’s times when they’re needed and times when they aren’t (See “No the Z-Pack won’t treat the Flu”, and “SuperChickens?” for the latter), but we’re going to ignore those occasions. We’ll assume that your doctor is well educated on the dangers of antibiotic resistance and not only knows when to prescribe antibiotics and when not to, but even knows how to choose which antibiotic to prescribe. So the doctor sends you off to the pharmacy with your prescription and very clear instructions: “Take every pill, on time, as directed, even when you start to feel better, and finish this prescription!” You get to the pharmacy, where the pharmacist hands you your prescription and tells you, very sternly, “Take every single pill, on time, as directed, even when you start to feel better, and finish this prescription!” You shake your head and go on your way, doubtful that you’ll ever feel better.

What they don’t tell you, or maybe they do, but you don’t hear, because you’re all very busy people, is why you have to take every single pill on time and finish the prescription, as directed, even after you start to feel better. They don’t tell you about what the antibiotics do to the bacteria inside your body, or what the bacteria do in response. So you start taking them, because anything would be better than how you feel now. Every hour, though, you start to recover, and it doesn’t take more than a few days, maybe even just 2, before you’re having trouble remembering those pills. Especially if they’re big. Or you have to take them two or three times a day. Or both. Oh yeah, I know how it is. I’ve been there. And you forget. And you start feeling better. And you decide it won’t hurt to save them for the next time you get sick – save the copay, right?

Except, here’s what you might have learned if everyone hadn’t been too busy to tell you why you have to take the pills the way they tell you. Every day in your body, evolution is pushing bacteria forward to be better, stronger, more fit for survival. The ones that successfully reproduce, that divide to make another copy, to increase the population of bacteria, those are the fittest. They’re the best. You have bacteria that live inside of you, on you, around you, as a part of you. It’s your microbiome, and it’s shaped by everything you do, everything you eat, every move you make, and also by choices your parents made when you were tiny. In fact, there are more cells in and on you that are part of your microbiome than there are cells that are actually you. These cells are responsible for teaching your immune system how to respond to pathogens, they teach our bodies tolerance, they allow digestion of certain foods, and in some cases, the presence of one helps prevent the excess of another. Microbes are your friends.

But you’re sick, and you dislike microbes at the moment. There’s nothing wrong with that – you managed to get hold of a pathogenic microbe, a disease-causing bacteria that was stronger, more fit for survival, than the ones already present inside you. When your immune system met this bacteria, it started fighting. You’ve probably got fever, inflammation, and pain. Depending on where the infection is, you might have some sort of discharge – sinus infections produce nasty mucous, skin infections produce pus, etc. There might even be swelling. All of this is part of your immune system rushing to fight off the microbial invaders. If you weren’t miserable, you’d be dying. That would be worse.

So the doctor, who wisely knew which antibiotic to prescribe because tests determined which bacteria caused the infection, gave your immune system a boost. The antibiotic is chemical warfare. Or, if you dislike that imagery, antibiotics are assistants for immune cells. They come in and target bacteria specifically. In fact, most antibiotics work by targeting things in bacteria that the human (or animal) body lacks.

But we come back to the problem of susceptibility and evolution now. If the doctor writes a prescription for an antibiotic that targets Sal, but the bacteria making you sick is Jim, that antibiotic isn’t going to do much to make you better. If the doctor decides to write a prescription that will kill Sal, Jim, and Sue, then the antibiotic may well make you better, but it also risks making you sick when the balance in your body is thrown off (that’s why there’s a pro-biotics craze, and why, any time I take an antibiotic of any kind, I eat yogurt).

I said the doctor had prescribed the right antibiotic, so it was Sal making you sick, and the antibiotic is for Sal, not Jim. Let’s say you managed to get some bad chicken because a new guy at the local fast food place accidentally cooked the chicken in the fish vat, and it didn’t cook long enough or hot enough to kill the Salmonella inside the chicken, and you got sick (these things happen). Your immune system does what it can, but Sal just overwhelms you. The first antibiotic makes it in, and the sulfa drugs help wipe out everything in their path. But it only takes an hour or two for Sal and his family to reproduce (versus the 10 months that humans are pregnant, and the 11-15 years it takes to reach sexual maturity after birth). So if you ate one piece of chicken at 6 pm with just one bacteria, in 12 hours, there are 4096 bacteria in your system. That might be enough to make you sick. But 12 hours after that, when there are 16 million bacteria in your system, your immune system starts struggling to keep up, and you got sick. So the assistance of the medication is welcome, but it’s fighting millions of bacteria. If you waited 3 days to get to the doctor, Sal had the chance to make over 4 sextillion copies of himself before the antibiotics got on board (that’s a 4 with 21 zeros behind it, or 4,000,000,000,000,000,000,000). That’s starting with one bacteria, doubling every hour, for 72 hours.

OK, so let’s think about this for a minute. Four sextillion copies. The bacteria made a copy of itself every hour. Changes had to creep in. Not all at once, mind you, not big ones. But a copy of a copy of a copy starts to look pretty bad, and once you’ve copied a copy 72 times, even the best copier isn’t going to be perfect. So now there’s copies out there with little changes. Some of them will make absolutely no difference. In fact, odds are good that lots of them will make no difference. The whole process of DNA to RNA to protein is set up to allow for a certain amount of wiggle room, so that when little changes creep in, there’s room. But there’s only a little bit of wiggle room, and there’s been lots of wiggling. So there will have been changes that were bad for Sal’s offspring. Some of the four sextillion new Sals just aren’t as strong as Sal was. The immune system will get to them and take them out, if the immune system can just reach them (that’s a lot of cells. Good thing you have diarrhea. You’re getting rid of a lot of cells).

But in all of those wiggles, some of the wiggles will make some of Sal’s offspring more likely to survive. When the immune system comes looking, these new Sal Jrs have wiggled just enough to be able to hide better, or duck better, or fight better. They live where Sal died. And every hour, when the four sextillion cells divide, those changes get passed on. The weak ones die out, the Sals and Sal equivalents keep going, and the SuperSals keep getting stronger.

That’s when you take the first antibiotic. It takes 20 minutes to hit your system, and it wipes out the weaklings and a fair sized chunk of Sal and his buddies. It may even wipe out some of the SuperSals. Your immune system gets room to work, helps wipe out more weaklings, more Sals, and so on. But every hour, the survivors divide and make more. Your next dose of medicine comes after the Sals have had 8-12 generations to adapt to what you just threw at them. That’s not much, and the meds do a great job of killing off more, but every single time, guess who survives? That’s right – the strongest. The Super-Sals. The ones who know how to survive against the very medicine you’re taking.

Now, if you do what the doctor told you to do, and you take every pill on time, even when you feel better, and you finish your prescription as directed, then the antibiotics help your immune system do what it was struggling to do alone, and your body wipes out the infection, and eventually, may even get around to killing the super-sals. But what if you quit? What if, when you started feeling better, you stopped taking the pills? What happens then?

Oh, you feel better. You gave your immune system room to work, and it did a great job. But you didn’t finish the job. You quit before you were done, and you left the strongest to survive. The only bacteria left alive in your body now are resistant to the drugs you were taking. You quit, thinking you were ahead, but the truth is, you gave them exactly what they needed to take you out, because now, the doctor doesn’t have the tools needed to treat you when you get sick again. And you will – the new generation of SuperSals are going to keep growing and dividing. And every generation will have those wibbly wobbly errors. Yes, some will make them weaker, and even kill them, but most will not. Most will keep them SuperSals. And some will make them even stronger. Because you quit.

Which is why, my dearest friends and families, when you take antibiotics, I will hound you to take every single pill, on time, until the prescription is gone, as directed. Because otherwise, you’ve quit at the deadliest possible time. You’ve handed the bacteria everything they needed to become even more resistant to even more drugs – and to make you sicker still.

What if you do take your antibiotics like you should, but your doctor gives them for the flu? Watch for “No, the Z-Pack won’t treat the Flu”. And for more on antibiotic free meat, look for “SuperChickens?”

Antibiotics are less than 100 years old. That means there are people alive today who were born when mothers and infants still died of childbed fever, or streptococcal infections. While the risk of infection remains, the use of antibiotics has almost completely eliminated the risk of death due to infection during childbirth.
Likewise, before World War II, soldiers didn’t have to receive a mortal wound to die during war. Injuries and illnesses that we now treat with 5-10 days of antibiotics took the lives of soldiers, nurses, doctors, and civilians. In 1936, the son of president Franklin Delano Roosevelt lay on the edge of death, until an experimental treatment with the first commercially produced antibiotic wiped out the streptococcal infection in his body. Prontosil would earn its discoverer, Gerhard Domagk, a Nobel Prize for Medicine in 1939. Penicillin, the first natural antibiotic (derived from the fungus Penicillium, found growing on a forgotten petri plate in the lab of Alexander Fleming where it inhibited microbial growth), became available in the 1940s.
These miracle drugs helped wipe out the terrible scourges that had plagued mankind for centuries, including combating a disease so prevalent it had multiple names based on which symptoms manifested. Infection with Mycobacterium tuberculosis could cause consumption, or phthisis, as so many knew what we call simply TB. It could also cause terrible inflammation in lymph nodes and produce scrofula, creating a chronic mass in the neck that might eventually form a sinus and then an open wound. The introduction in 1946 of streptomycin, an antibiotic for tuberculosis, gave patients an option that wasn’t isolation or surgery to treat their disease.
Today, however, streptomycin is no longer an option for TB patients. Though you will hear of patients with penicillin allergies, it is rarely, if ever prescribed. Instead, when doctors and pharmacists refer to penicillin allergies, they’re referring to the class of drugs derived from penicillin, drugs which are chemically similar in structure, but not identical. Allergies aren’t the issue, either. Resistance is.
Let’s address what these two mechanisms are so that you can understand the problem before us. Drug allergies occur when the patient taking a medication has an immunological response to the medication. The patient’s body has inappropriately formed antibodies against the drug (or, if the drug is too small, as with haptens, the body has antibodies against the protein produced when the drug binds to its receptor in the body). These antibodies then attack the body whenever the drug is present – no drug, no reaction. Every time the drug is given, the body overreacts, and every time is worse than the time before. The rule of thumb for allergies is simple: The first time is free, but the price you pay escalates every time after.
Resistance, however, occurs within the bacteria, the organisms being targeted by the drug for elimination. All bacteria carry their basic genetic code within them, just like all humans do, and all cows, sheep, dogs, chickens, pigs, ducks, bugs, corn, grass, mushrooms, etc. In that way, we’re all alike. But bacteria have a means of packing extra information inside, little bonuses. These little bonuses are extra pieces of DNA called plasmids, and while they can be packaged in with the rest of the genetic code of the bacteria, they don’t have to be. They can be just tiny little circles of bonus features tucked inside, waiting to be shared.
Plasmids carry things like fertility, which is sort of a misleading term, since bacteria don’t reproduce the way people do. All bacteria are clones – they just copy themselves and then bud off the copy, resulting in two identical cells from one. There’s no need for fertility for that. No, fertility plasmids allow a structure called a pili to be extended from one bacteria to another, and the one who sends the pili can then send a plasmid. Now the second bacterium has a plasmid for fertility, too.
Let’s make this a little easier to see. I’m going to rephrase this as an analogy, a story between Sue, Jim, and Sal. Even though all bacteria reproduce asexually and thus are called mother and daughter cells, we’re going to call our bacteria “Sue” ,“Jim”, and “Sal”.
Sue is a very happy Streptococcus. She’s living life just like all her mother did and her sister and the mothers and sisters before her – synthesize DNA, transcribe DNA into RNA, translate the RNA into amino acids which assemble into peptides and fold into proteins that Sue can use to do everything Sue needs to survive. Good Sue.
Jim’s a peachy keen Escherichia. He has no idea he smells bad (and poor guy, he reeks). He just goes through life, just like Sue, just like his mother and his sisters, synthesizing DNA, transcribing it, translating it, using his proteins…
As Jim happens to be carried past Sue by the current today, Sue’s proteins have made a pili. In and amongst her DNA is a plasmid for pili, and that’s one of the ones she’s expressing. It brushes against Jim, and the two cells connect. As soon as that happens, Streptococcus Sue’s plasmid starts to travel down her pili to Escherichia Jim’s cell. It doesn’t matter that they’re different kinds of cells. She’s got a pili and she’s got a plasmid, and bacteria love to share.
The current didn’t stop, of course, and the connection was always tenuous, so it’s not long at all before the pili breaks loose. Sue goes back to drifting along. She’ll probably make contact with some of Jim’s siblings, and her siblings will probably make contact with Jim – bacteria love to share, and they don’t like to be alone. By the end, Sue’s plasmid has made it not just to Jim but probably to several of his siblings, but we’re going to leave poor Sue behind.
Jim finds his new plasmid and plugs it in. This is nifty stuff. Now he can make a pili, too! He practices. As he’s drifting along in the current, extending his new pili, Jim encounters Sal, the Salmonella (Yeah, yeah, on the nose, whatever). Sal also has a pili, but Sal has a different kind of plasmid to share with his pili plasmid. Sal knows how to fight off sulfa-antibiotics. Bacteria like to share. Sal shares this plasmid, this resistance to sulfa-drugs, with Jim, with all of Jim’s siblings, and now, every bacteria Jim encounters will also gain resistance to sulfa antibiotics. It didn’t matter that Jim and Sal were different kinds of bacteria, or even that Jim didn’t care about Sulfa antibiotics. Jim is a bacteria, and Bacteria Share.
In the 90 years since penicillin was discovered, bacteria have shared resistance to it so extensively that it is largely useless. In the 70 years since streptomycin’s introduction, bacteria have shared resistance to it so extensively that it is largely useless. Bacteria Share. They share with every bacteria, and they do it faster than we can fight them, faster than we can find new drugs, terrifyingly fast. But that’s not why we may lose the single greatest weapon we’ve had in the war on disease in the past century.
If all we were fighting was the fact that Bacteria Share, we could deal with that. The bigger issue comes when you and I help the bacteria. Stay tuned for “SuperChickens?”, “Quitting when you’re not really ahead”, and “No, the Z-Pack won’t treat the Flu”.

It’s the title of a science fiction horror film, but it’s also a real occurrence for certain insects. In this video (another LinkedIn find) from the BBC, we meet cordyceps, a fungal infection that controls and eventually kills ants. This is a 3 minute clip from the longer Planet Earth series. If you’ve never seen this remarkable series, I highly recommend it. Not only do I enjoy it, I’ve found that even my pets enjoy it, too (yeah, I know, that’s silly).

In another link from LinkedIn, we have a story about a study started 12 years ago, in Africa. In the US, iron supplementation is a common part of pregnant women’s life; the benefits to the developing child can’t be overestimated. In Africa, many children suffer from iron-deficient anemia. It seemed a natural solution to supplement the diet with iron supplements and other vitamins. However, during the study, more children on the supplement died than those not on the supplement, bringing the study to an abrupt and early end.

I’ll let you read the story for yourself; the reasons for the confusing results still aren’t entirely understood, but are being sought out in order to hopefully correct both the nutrient deficient and the fatal result of correcting it in areas where malaria is endemic. I highlight it, however, not only because it’s another LinkedIn story, but because it serves as an excellent reminder of the law of unintended consequences: solving one problem may cause another, or several others. While this is a large-scale example of unintended consequences, even in your lab work, you may encounter the same problems. Look for more detail on this idea in future posts.

Today’s a twofer! Today’s LinkedIn video reminded me of the paper I presented for my pathology class (which was more like a journal club). Both deal with the study of fruit flies (Drosophilia sp.) in space. The video focuses on the role of the flies in studies on the ISS in space, while the paper focuses on a specific study done in 2006 and the probable importance of that study.

Specifically, the paper focused on the way that changes to gravity during the development of Drosophilia sp. resulted in altered immune pathways, leading to specific weaknesses in those flies raised in a microgravity environment. This finding in a model species (one that can be used to illustrate how humans work, but on a simpler scale), may help explain why many astronauts are more prone to illness upon return from space and may also help provide clues for how to counter the impact of gravity on immunity in the future.

Today is 4 July, and it happens to be the 237th birthday of the United States of America. Many Americans will celebrate this historical occasion with a cold beer and lots of bright fireworks (or applied microbiology, biochemistry, chemistry, and physics!). In honor of history, microbiology, and beer, I present another LinkedIn link: